Regulation of Mammary Carcinoma Cell Polarity and Invasion by Syndecan-1

Syndecan-1 (Sdc1) is expressed in the mammary epithelium and is expressed by cultured human mammary carcinoma cells. The signaling activity of Sdc1 on these cells lines is being examined both by overexpressing Sdc1 and by silencing its expression using short interfering RNA (siRNA) oligos. These experiments show that Sdc1 is involved in the morphogenesis and the proliferation of the cells. Silencing Sdc1 expression affects the proliferation of both normal mammary epithelial cells as well as the carcinoma cells. In addition, the level of expression of Sdc1 affects the invasion and morphogenesis of the mammary cell lines. The MDA-MB-231 human mammary cell line is a highly invasive carcinoma. This invasion is recapitulated in three-dimensional matrices such as matrigel and type I collagen gels. In unpublished work, we have found that overexpression of mouse Sdc1 in the MDA-MB-231 cells causes them to revert from the invasive phenotype to a cohesive phenotype more typical of normal mammary epithelial cells, which form cohesive acinar structures in the gel. However, this reversion is observed only in matrigel, suggesting recognition of a specific matrix component in the matrigel is necessary for the Sdc1 regulatory activity. This hypothesis has led to our current understanding that Sdc1 regulates one part of the signaling pathway downstream of the α3ß1 integrin. Via this mechanism, Sdc1 affects the activity of the small GTPase Rac and the distribution of PI-3K at cell adhesion sites. We are currently studying which domain(s) of the Sdc1 protein are necessary for this regulatory mechanism and the molecular details of the interaction and signaling pathway.

References:
• Burbach, B.J. and Rapraeger, A.C. (2004). Syndecan-1 ectodomain regulates matrix-dependent signaling on mammary carcinoma cells. Exp. Cell Res., 300: 234-237.
• Beauvais, D.B. and Rapraeger, A.C. (2004). Syndecans in tumor cell adhesion and signaling. Reprod. Biol. Endocrin., 2:3 (http://www.rbej.com/content/2/1/3)